Study on Inborn and Outborn Neonatal Admissions in Relation to Gestational Maturity in Neonatal Intensive Care Unit at a Tertiary Care University Hospital in Upper Egypt

Neonatal morbidity and mortality rates indicate a country's socioeconomic status and the quality, and effectiveness of its health care system. This research aimed to identify the clinical pattern and causes of neonatal admission for inborn and outborn babies in a tertiary care university hospital and their outcomes. Over a year, this prospective hospital-based research was conducted in the neonatal intensive care unit (NICU) of Assiut Children's Hospital in Upper Egypt (January 1st to December 31st, 2020). Gender, birth weight, gestational age, postnatal age, delivery mode, delivery place, admission cause, hospital stay period, and neonatal outcomes were collected. A total of 1,638 newborns were admitted; 930 (56.8%) were preterm and 708 (43.2%) full-term. Inborn admissions were 1,056 (64.5%) and outborn 582 (35.5%). The majority of inborn admissions were preterm 726 (68.8%), and outborn were full-term 378 (64.9%). The commonest admission causes among inborn and outborn preterm infants were respiratory distress syndrome (84.3%) and congenital intestinal obstruction (22.5%), respectively, while multiple congenital anomalies were the commonest cause for admission among both inborn and outborn full-term babies. The mortality rate was 708 (43.2%), higher among inborn (50%) versus outborn (30.9%). The leading cause of death was respiratory distress syndrome among premature inborn with case fatality rate of (56.9%) and multiple congenital anomalies among premature outborn (60%), as well as inborn (67.4%), and outborn (42.6%) full-term neonates. In conclusion, the neonatal mortality rate was high among studied cases. Morbidity and mortality of respiratory distress syndrome and congenital anomalies were alarmingly high. Therefore, all health care providers must devote a considerable effort to improve health care delivered to these neonates.


Introduction
Since it is vulnerable to high mortality and morbidity, neonatal time (first 28 days of life) is important in life. 1 Over the last few decades, advances in neonatal care greatly improved the newborns' survival rate, especially premature newborns. So, neonatal admissions and resulting neonatal diseases are rising. 2 Neonatal intensive care unit (NICU) admissions place a significant financial and social burden on health care facilities and families, also, disease patterns differ from location to location and with time, even in the same place. 3 Every year, approximately nine million children die in the perinatal and neonatal period across the world, with nearly all of the mortality occurring in developing countries (98%). Neonatal deaths are responsible for 40 to 70% of all infant deaths. 4 Evidence on neonatal mortality in developing countries is limited, and risks are poorly defined. The neonatal mortality rate (NMR) in Egypt in 2013 was 11.8 per 1,000 live births-approximately 54% of all mortality in children under the age of 5 years. 5 Based on WHO statistics, there were 2.5 million infant deaths worldwide in the first month after birth; 7,000 neonates died per day, with about one-third dying in the first 24 hours of life and approximately 75% in the first 7 days after birth. Moreover, the rate of neonatal death decreased more slowly, compared with that of children aged 1 to 59 months. 6 Worldwide, premature birth (27%), infection (26%), perinatal asphyxia (23%), and congenital malformations (7%) are the leading causes of neonatal deaths. 7 Other authors reported low birth weight, prematurity, sepsis, low Apgar scores, respiratory distress syndrome (RDS), low socioeconomic status, delivery by cesarean section, and postnatal age on admission are risk factors linked with mortality in the neonatal period. 8 Researchers reported that the primary reasons for 78% of all non-malformation-related mortality in preterm babies were RDS, severe perinatal asphyxia, and infections. Other reasons for newborn deaths were bronchopulmonary dysplasia (4%), intraventricular hemorrhage (3%), pneumothorax (2%), and necrotizing enterocolitis (2%). 9 In developed countries, newborns mostly die due to unpreventable conditions, such as congenital malformations, while most neonatal deaths in developing countries are due to preventable reasons, such as birth asphyxia, infections, and prematurity. 10 Evidence-based information on neonatal morbidities, mortalities, and interventions, particularly facility-based care are critical for implementing newborn preventive health strategies to decrease neonatal deaths.
As a result, this research aimed to evaluate the profile of inborn and outborn newborns admitted to a tertiary care referral and teaching hospital in Upper Egypt, as well as to evaluate their outcomes.

Methods
This hospital-based prospective observational study was performed over a period of 1 year from January 01, 2020 to December 31, 2020 in the NICU of Assiut University Children's Hospital. This hospital provides health care services for people in the Assiut governorate and its surrounding communities in the urban and rural areas in Upper Egypt. It is equipped with all facilities toward being one of the main referral hospitals in Upper Egypt. The NICU provides services for approximately 145 newborns per month with a total of 50 incubators and has facilities dedicated for outborn and inborn care. It serves the obstetrics department of Women's Health Hospital which is one of the Assiut University Hospitals and their delivered newborns needing admission (inborn). Furthermore, it receives outpatients, who are referrals from primary health centers, or from a diversity of places (outborn). Although our hospital serves five governorates in Upper Egypt-each one including approximately 2 million people-there are no specific data for live births and population in the surrounding referral region, due to the poor registration system in such places,

Study Population and Sampling Size
All inborn and outborn newborns that were admitted to the NICU during the research period were included in this study.

Data Collection Tools
Detailed information for each of the neonatal admissions was taken including gender, delivery mode, delivery place, gestational age, birth weight, age at admission to NICU, length of hospital stay, maternal risk factors, causes for admission, reasons for neonatal mortality, and outcome of admitted cases. The hospital has a standard protocol for the diagnosis and management of neonatal conditions. The diagnosis was mostly clinically supported by laboratory investigations, radiological imaging, and echocardiography when needed.
In our hospital, almost all neonatal conditions have been protocolized for diagnosis and management of different neonatal diseases as neonatal sepsis, necrotizing enterocolitis, respiratory distress, neonatal seizures, and hyperbilirubinemia. In our neonatal unit, plain X-rays, transcranial ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI) scan, echocardiography, barium studies, and electroencephalography (EEG) can be done.

Ethical Issues
The research was approved by the Local Ethical Committee Institutional Review Board (IRB) of Assiut University Hospital, Assiut, Egypt (IRB: 17100776, December 29, 2019) that was according to the Declaration of Helsinki. Informed written consent was obtained from mothers or guaranteed of every participant before inclusion, after explaining the research aim to them at admission.

Statistical Analysis
Data were analyzed by Statistical Package for Social Sciences version 23 (IBM SPSS, IBM Corp., Armonk, New York, United States). Values were presented as mean AE standard deviation of number (%) as appropriate. During univariate analysis, the categorical values were tested with Pearson Chi-square and Fisher exact test as appropriate. p-Values less than 0.05 were considered statistically significant.
►Table 2 shows the baseline characteristics of the studied preterm and full-term babies. Preterm babies represented 930 (56.8%) of them (726, 78.1% inborn, 204, 21.9% outborn), male babies were 490 (52.7%), and majority of cases were delivered by CS 762 (81.9%). With regards to weight on admission and gestational age, 75.3% of cases were in the category of 1 to 1.5 kg, and 74.9% in the category of 28 to 32 weeks. Regarding age at admission, majority of preterm cases were admitted in first day of life 740 (79.5%). Based on duration of hospital stay, more than half of the cases, 511 (54.9%) stayed for 7 to 15 days. According to maternal risk factors, preeclampsia was considered the most common risk factor among studied preterm cases. There were statistically significant differences between inborn and outborn preterm newborns in the mode of delivery, postnatal age at admission, duration of hospital stay, and maternal risk factors (p ¼ 0.001, p ¼ 0.001, p ¼ 0.001 and p ¼ 0.007, respectively). Full-term babies were 708 (43.2%), among which 330 (46.6%) were inborn and 378 (53.4%) were outborn, male babies were 375 (53%), and majority of the cases were delivered by CS (585, 82.6%). With regard to the weight on admission; majority of cases 610 (86.2%) were in the category of 2.5 to <4 kg. Considering the age at admission, about one-half of cases (356, 50.3%) were admitted within the first day of life. Based on the hospital stay duration, 408 (57.6%) stayed for 7 to 15 days. According to maternal risk factors, premature rupture of membranes (PROM) was the most common risk factor among full-term cases. There were statistically significant differences between inborn and outborn full-term newborns in postnatal age on admission, duration of hospital stay, and maternal risk factors (p ¼ 0.001, p ¼ 0.001 and p ¼ 0.001, respectively).

Discussion
Morbidity and mortality data obtained from regular registration are beneficial for both health care providers and researchers to propose interventions for prevention, treatment, and adjusting the quality of care. In the present study, preterm babies represented the majority of neonatal admissions, (56.8% of which 78.1% were inborn and 21.9% outborn) while full-term babies represented 43.2% (46.6% inborn and 53.4% outborn). The majority of admitted neonates were inborn (64.5%), with an inborn to outborn ratio of 1.8:1. In Egypt, at Zagazig University Children Hospital, Abd el aziz et al 11 reported that preterm were higher than full-term neonates (55.9 vs. 44.1%) and inborn were higher than outborn neonates (83.1 vs.16.9%). A study done by Fahmy et al 12 at Cairo University Hospital showed that majority of inborn admitted were premature (72.5%) while majority of outborn admitted were full-term (67.7%). On the contrary, at Addis Ababa, Ethiopia, Tekleab et al 13 reported that 39.8% of neonatal admission were preterm while majority (60.2%) were full-term.
Our results showed that, most cases delivered by CS (82.2%), which matched with the Egypt demographic and health survey (EDHS) 2014, 14 that reported 87% of all live births were delivered in a hospital and slightly more than half of births (52.0%) were delivered by CS. On the contrary, Bokade and Meshram 15 and Verma et al 16 showed different results as 31.9 and 30.4% were born by CS, respectively. This may be explained by increasing emergency CS in tertiary Gynecology/Obstetric hospitals that receive high-risk pregnant women.
In this study, males were more than females (52.8 vs. 47.2%) which was similar to others. 17,18 This could be a reflection of some cultural beliefs where the male baby is preferred to female and more likely to be paid attention when he was ill.
Our results showed that the majority of neonatal admissions were in the first day of life (79.5% preterm, and 50.1% full-term). Similarly, Seboka et al 19 showed in their research that most newborns were admitted during first 24 hours following birth (76%). Also, our results were consistent with others. 20 As this is a transition from intrauterine to extrauterine life, majority of neonatal issues may arise within the first 24 hours after birth. 20 The commonest cause for admission in this study among preterm babies was RDS (69.1%), followed by congenital intestinal obstruction (6.2%), neonatal jaundice (4.5%), and sepsis (4.1%). Furthermore, the commonest cause for hospital admission among full-term babies was multiple congenital anomalies (25.4%), followed by neonatal jaundice (15.3%),  congenital intestinal obstruction (15.3%), transient tachypnea of newborn (9.3%), neural tube defects (6.8%), and sepsis (6.2%). A similar study carried in the NICU at Zagazig University Children Hospital, Egypt, reported that the commonest diagnosis during NICU admission was RDS (21.1%) followed by surgical causes (14.6%), late onset sepsis (12.2%), and congenital pneumonia (8.5%). 11 A recent study conducted in Qena (Upper Egypt) reported that the incidence of respiratory distress in neonates was 46.5%. Mean gestational age of the newborns was 34.49 AE 3.31 weeks. Commonest causes of respiratory diseases were RDS (49.6%) transient tachypnea of newborn (22.0%), neonatal pneumonia (17.2%) and meconium aspiration syndrome (6.2%). 21 Elizabeth and Oyetunde 22 reported that congenital anomalies were the most frequent cause of morbidity among studied neonates (7.22%)musculoskeletal defect (33.33%) being the commonest congenital anomaly amongst them. Eze et al 23 showed that the main neonatal morbidities were prematurity and its complications-neonatal jaundice, perinatal asphyxia, and neonatal sepsis. Prematurity complications and perinatal asphyxia were responsible for approximately one-third of NICU admissions each and were the most predominant causes of neonatal morbidity. A study done in Nigeria showed premature low birth weight (54.8%), birth asphyxia (19.2%), respiratory distress (6.7%), sepsis (5.3%), congenital malformations (1.2%), and neonatal jaundice (1.1%) as main reasons for admission. 20 Research in Pakistan 24 showed that preterm low birth weight newborns (24.6%), meconium aspiration syndrome (15.2%), birth asphyxia (17.0%), sepsis (19.9%), RDS (18.9%), and neonatal jaundice (9.44%) were the common causes for admission. The overall neonatal mortality in this study was 708 (43.2%). In preterm cases, 462 (49.7%) died, with inborn admissions accounting for majority of deaths (53.7%). On the other hand, 34.7% of admitted full-term cases died, inborn admissions accounting for deaths in majority (41.8%). These results were higher than other studies conducted in Egypt which showed that the NMRs among cases admitted to the NICUs in Zagazig University Hospital, 11 Benha University Hospital 25 and Tanta City Hospitals 26 were 19.2, 30.6, and 27.7% (of the studied neonates), respectively. In our study, higher morbidity and mortality rates due to congenital anomalies may be explained by the increased referral of such cases from other health care centers, since there is a neonatal surgical unit considered as a referral unit for critically ill neonates with surgical diseases. Also, management of congenitally abnormal neonates needs advanced facilities and skills, which are not available sometimes in many centers. Similar to our work, Fahmy et al 12 in Cairo University hospital, Egypt found that the majority of their inborn deaths were preterm (78.48%), also deaths were significantly more among inborn than outborn (37.2 vs. 17.2%, p < 0.001). This could be due to the increasing number of inborn hospital admissions for preterm babies and also that admitted babies' status in outborn NICU is better, with favorable outcome. Omoigberale et al 27 reported that the high cost of caring for a newborn may be responsible for delay in presentation as well as delay in administering care, resulting in poor neonatal outcome.
In our study, the commonest reason for mortality among premature newborns was RDS with a case fatality rate of 56.7%, that was matched with results of studies conducted by Verma et al 16 and Raikwar. 28 These studies stated that the commonest causes of death were prematurity with RDS, sepsis, and perinatal asphyxia. On the contrary, Abd el aziz et al 11 found that sepsis (63.41%) followed by respiratory failure (26.82%), and cardiogenic shock (14.63%) were the commonest cause of death among studied neonates, Their results also agreed with studies done by Muthukumaran,29 and Medhat and Khashana. 30 In the current study, multiple congenital anomalies were the main reason of death among inborn and outborn admitted full-term infants, with case fatality rates of 67.4 and 42.6%, respectively, followed by perinatal asphyxia, congenital intestinal obstruction, meconium aspiration syndrome, and sepsis. Andegiorgish et al 31 found that congenitally malformed neonates were three times more likely to die than their counterparts, similar to other research in which most neonates with congenital malformation died. 31 In the present study, the morbidity and mortality caused by neonatal sepsis was low. Only 23 cases with sepsis were recorded. This low number could be due to solid infection control measures applied at our hospital, with increased awareness among health care providers. Moreover, sepsis could be underestimated in this study because septic cases were limited to only those diagnosed at admission. The difference between our study and others, in Egypt and India, regarding high neonatal morbidity and mortality rates is explained by the fact that our hospital as previously described, is considered a high referral center for surrounding governorates. Besides patients in complicated forms due to delayed presentations and poor management, the poverty in Upper Egypt, high cost of caring for a newborn, and low educational level have also contributed to bad outcomes in our locality. In our study, there were no confirmed neonates with COVID-19; instead, three asymptomatic cases were suspected of having COVID-19 due to positive maternal infection but were found to be negative after laboratory examination. According to Wang et al, 32 there is no definite evidence of intrauterine vertical transmission of SARS-CoV-2, but more high-quality research is needed. Although virological and serological evidence is useful in clarifying this issue, scientifically sound and trustworthy assays should be utilized, and newborns should be followed for 6 to 18 months after birth to draw meaningful conclusions when serological results are employed.
For assessing the effectiveness of treatment given in a hospital environment, knowing the admission outcomes is critical. Among NICUs in various parts of the world, NMRs vary dramatically. This disparity is most likely due to differences in the attending population, antenatal treatment, admission requirements, unique exclusion and inclusion criteria, and neonatal care given.

Limitation of Study
This study was performed at a tertiary care and referral hospital where most of the patients were critically ill and complicated. Thus, results of our work may not reflect the true morbidity and mortality burden prevalent in the community as a whole.

Conclusion
RDS, prematurity, and congenital malformations were significantly linked with neonatal mortality in Neonatal Care Unit of our hospital. For controlling local neonatal deaths, one should prioritize early management of low birth weight, preterm births, and neonatal complications. The most common causes of neonatal deaths are preventable and treatable; careful assessment and risk detection are the best ways to minimize neonatal mortality in our community. The incidence of congenital malformations in our resource-limited setting is high and antenatal diagnosis rates are very low.

Recommendations
This study revealed that the majority of inborn admissions were preterm babies and RDS was the commonest cause of morbidity and mortality in these babies. Thus, this study recommends administration of antenatal corticosteroid therapy for women at risk of preterm birth from 24 to 34 weeks of gestation, starting continuous positive airway pressure therapy at diagnosis, and early surfactant replacement therapy (within first 2 hours after birth) for preterm neonates with established RDS. To improve the mortality for neonates with congenital anomalies, this study recommends referral of mothers who are suspected to deliver a baby with extreme low birth weight (<1,000 g), anomalies needing immediate surgical interventions, and life-threatening anomalies to a hospital with level IV NICU (University Hospitals). Regarding outborn neonatal admissions, access to high-quality and timely care for preterm and sick newborns are critical to improving outcomes. The goal is to reduce neonatal mortality and morbidity when the management of a sick infant exceeds care level ability provided in a district hospital. Communication with the referral center must be done prior to transport to ensure availability of beds and services required for babies (e.g., surfactant, surgery). Provision of ambulance services with trained staff for newborn referrals could improve health outcomes of preterm and sick newborns. Sensitization and training of health care providers on national referral protocols/guidelines, setting expectations for adherence, government investments in newborn referral systems, and standardizing initiating and receiving facility referral communication, are all urgently needed. Upgrading provision of newborn care at lower-level facilities will decrease referral load at higher-level facilities.